Running title: Regulation of Proximal Tubule Na transport Contact address

100 yrs ago Starling articulated the interdependence of renal control of circulating blood volume and effective cardiac performance. During the past 25 years the molecular mechanisms responsible for the interdependence of blood pressure (BP), extracellular fluid volume (ECFV), the renin angiotensin system (RAS) and sympathetic nervous system (SNS) have begun to be revealed. These variables all converge on regulation of renal proximal tubule (PT) sodium transport. The proximal tubule reabsorbs 2/3 of the filtered Na+ and volume at baseline. This fraction is decreased when BP or perfusion pressure is increased, during high salt diet (elevated ECFV) and during inhibition of the production of AngII; conversely, this fraction is increased by AngII, SNS activation, and low salt diet. These variables all regulate the distribution of the Na+/H+ exchanger isoform 3 (NHE3) and the Na+-phosphate co-transporter (NaPi2) along the apical microvilli of the PT. Natriuretic stimuli provoke the dynamic redistribution of these transporters along with associated regulators, molecular motors and cytoskeletal associated proteins to the base of the microvilli. The lipid raft associated NHE3 remains at the base and the non-raft associated NaPi2 is endocytosed culminating in decreased Na+ transport and increased PT flow rate. Anti-natriuretic stimuli return the sam